Children with Fetal Alcohol Spectrum Disorder (FASD) exhibit cognitive, neuropsychological and neurobehavioral problems that range from mild to severe. Moreover, secondary disabilities in a number of life domains are common, including a high incidence of depression and anxiety disorders. Hypothalamic- pituitary-adrenal (HPA) dysregulation is a common finding in major depression. Furthermore, there is a strong relationship between depression in adulthood and adverse early life events. Consistent with these findings, brain areas implicated in depression overlap with areas that mediate the stress response, with the HPA axis a key player in both. We have shown that prenatal alcohol exposure (PAE) reprograms the fetal HPA axis such that HPA tone is increased throughout life. PAE offspring are typically hyperresponsive to stressors, and show both increased HPA drive and deficits in feedback regulation. Furthermore, interactions between the HPA axis and both the gonadal and serotonergic systems are altered by PAE. This pattern of dysregulation parallels in many ways what is observed in depression. The present proposal will utilize our well-established animal model of PAE to examine the links among PAE, stress system abnormalities, the gonadal and serotonergic systems and depression. In the context of the stress-diathesis model, we will test the hypothesis that fetal programming of HPA activity by PAE permanently sensitizes neuroadaptive mechanisms that mediate responses to stress, resulting in hyper- reactivity to subsequent, even mild, stressful life events. Ultimately, repeated stress exposure results in a maladaptive cascade of events and increased vulnerability to depression and anxiety. Our Preliminary Studies demonstrate sex-dependent increases in depressive symptomatology in PAE animals following exposure to chronic mild stress (CMS) in adulthood. The proposed studies will extend these finding in important and novel directions. Our Specific Aims are to investigate: 1) the role of the maternal hormonal milieu in programming fetal HPA activity, sensitizing the offspring HPA axis, and mediating increased vulnerability to adverse effects of stress on offspring HPA, brain and behavioural outcomes; 2) the role of HPA dysregulation in adult PAE males and females in mediating increased vulnerability to adverse effects of stress on HPA, brain and behavioural outcomes, and the role of the gonadal hormones in mediating the sexually dimorphic effects of PAE and stress that are observed; and 3) whether antidepressant treatment can reverse or alleviate the adverse effects of stress on HPA, brain and behavioural outcomes in PAE offspring. The proposed studies will elucidate mechanisms mediating the link between PAE and increased vulnerability to depression and anxiety disorders in children with FASD, and have important implications for the development of novel therapeutic interventions. PUBLIC HEALTH RELEVANCE Children with Fetal Alcohol Spectrum Disorder (FASD) exhibit cognitive, neuropsychological and behavioral problems, as well as numerous secondary disabilities, the most prominent being mental illnesses such as depression. The present research utilizes our well established animal model of prenatal alcohol exposure to examine the role of stress system abnormalities in mediating this increased incidence of depression. The data from these studies will significantly increase our understanding of the mechanisms underlying the long term and far reaching consequences of prenatal alcohol exposure on health and well-being, and will have important implications for the development of novel therapeutic interventions for depression in individuals with FASD.